The molecular cloning of the signal transducing receptors for fibroblast growth factors
has revealed a tyrosine kinase gene family with at least four members. Differential
splicing and polyadenylation creates further diversity in the FGF receptor system.
These numerous receptor forms have both distinct and redundant properties (Partanen et al. 1993).
NCBI Summary:
The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]
Tilly JL, et al 1992 reported that epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of
apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase-dependent
mechanism.
Chun SY, et al 1996 studied hormonal regulation of apoptosis in early antral follicles: follicle-stimulating hormone as a major
survival factor.
Incubation of follicles with epidermal growth factor (EGF) and basic fibroblast growth factor
maximally suppressed follicle apoptosis by 32% and 42%, respectively.
LaPolt PS, et al 1990 reported that basic fibroblast growth factor induction of granulosa cell tissue-type plasminogen activator
expression and oocyte maturation: potential role as a paracrine ovarian hormone.
Baird A, et al 1986 reported that treatment
of rat ovarian granulosa cells with FGF inhibits the capacity of follicle stimulating hormone to
stimulate estrogen production and to induce luteinizing hormone receptors. In contrast, although
incubations with FGF can inhibit the estrogen-sensitive component of progesterone synthesis, the
presence of FGF with suboptimal concentrations of follicle stimulating hormone significantly
enhances the synthesis of progesterone.
Expression and Function of Fibroblast Growth Factor 10 and Its Receptor, Fibroblast Growth Factor Receptor 2B, in Bovine Follicles. Buratini Jr J et al. Some fibroblast growth factors (FGF) affect ovarian follicle cell growth and/or differentiation. Whereas many FGFs activate several FGF receptors, FGF7 and FGF10 primarily activate only one, FGFR2B. As FGF7 is produced by bovine theca cells and acts on granulosa cells, we tested the hypothesis that FGF10 may also play a role in folliculogenesis in cattle. Reverse transcription-polymerase chain reaction demonstrated the presence of FGF10 mRNA in oocytes and theca cells of antral follicles, and in preantral follicles. FGF10 protein was detected by immunohistochemistry in oocytes of preantral and antral follicles, and in granulosa and theca cells of antral follicles. FGF10 expression in theca cells changed during follicle development; mRNA abundance decreased with increasing follicular estradiol concentration in healthy follicles, and was lowest in highly atretic follicles. Culture of granulosa cells in serum-free medium demonstrated regulation of FGF10 receptor expression by FSH. Addition of FGF10 to cultured granulosa cells decreased estradiol but did not alter cell proliferation. These data support a role for FGF10 in signaling to granulosa cells from theca cells and/or the oocyte.
Fibroblast growth factor 7 stimulates in vitro growth of oocytes originating from bovine early antral follicles. Cho JH et al. Essential factors required for growing oocytes derived from bovine early antral follicles and their mechanisms of action are poorly understood. Fibroblast growth factor 7 (FGF7) is a member of the heparin-binding FGF family with a distinctive pattern of target-cell specificity. The effect of FGF7 on the stimulation of oocyte growth in a culture of cumulus-oocyte complexes with granulosa cells (COCGs, oocyte diameter; 90-100 microm) was investigated. The oocyte diameter of COCGs was increased significantly in the FGF7-containing medium (10 ng/ml; 117.2 +/- 3.2 microm, 50 ng/ml; 116.5 +/- 3.5 microm) compared to the control (0 ng/ml; 110.5 +/- 2.8 microm) after 16 days. However, there was no stimulatory effect of FGF7 on the proliferation of cumulus-granulosa cells. The FGF7 receptor, fibroblast growth factor receptor 2IIIb (FGFR2IIIb), was detected in cumulus-granulosa cells from COCGs. Messenger RNA expression of FGFR2IIIb was induced to cumulus-granulosa cells by FGF7. The mRNA expression levels of KIT ligand (KITLG), KIT (KIT), growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) in the cultured COCGs were determined in FGF7-treated (10 ng/ml) cultures using real time RT-PCR analysis. The levels of KITLG and KIT, but not GDF9 and BMP15 mRNA expression were stimulated by FGF7. Furthermore, neutralizing antibody for KIT attenuated the stimulatory action of FGF7 on the oocyte growth. These results strongly suggest that FGF7 may be an important regulator for oocyte growth and its action is mediated via the KIT/KITLG signaling pathway. Mol. Reprod. Dev. (c) 2008 Wiley-Liss, Inc.
Expression regulated by
LH
Comment
Activated receptor tyrosine kinases in granulosa cells of ovulating follicles in mice. Schuermann Y et al. (2018) Successful ovulation requires the actions of gonadotropins along with those mediated by growth factors binding to their receptor tyrosine kinases (RTKs). There are several growth factors such as epidermal growth factor family ligands and interleukins that play a role during ovulation initiated by the preovulatory surge of luteinizing hormone (LH). The aim of this project was to analyze growth factor signaling pathways induced by LH in mouse granulosa cells. Immature female mice were treated with equine chorionic gonadotropin (eCG) followed 48h later by human chorionic gonadotropin (hCG) to induce follicular growth and ovulation. We performed protein array analysis where we identified higher phosphorylation of insulin-like growth factor 1 receptor (IGF1R), the fibroblast growth factor receptor 2 (FGFR2) and ephrin receptor B1 (EPHB1) in granulosa cells at 4h post-hCG compared to 0h hCG (P < 0.05). We report both a significant increase in transcript abundance (P < 0.05) and the phosphorylation level (P < 0.05) of the IGF1R in granulosa cells at hCG4h. The mRNA abundance of the Fgfr2 and Ephb1 receptors remained unaltered upon hCG treatment. Nonetheless, transcript abundance of the fibroblast growth factor 2 (Fgf2) ligand was elevated at hCG4h (P < 0.01). Based on these results we conclude that the preovulatory LH surge activates signaling pathways of IGF1R through increase in the expression of the Igf1r gene in granulosa cells of ovulating follicles in mice. The LH surge also appears to activate FGFR2 IIIc and EPHB1 signaling, although further investigation is required. This article is protected by copyright. All rights reserved.//////////////////
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Asakai R, et al 1995 reported protein kinase C-dependent down-regulation of basic fibroblast growth factor (FGF-2) receptor by
phorbol ester and epidermal growth factor in porcine granulosa cells.
Doraiswamy V et al reported that Fibroblast growth factor receptor (FGFR)-1 and -2 in the ovine corpus luteum
throughout the estrous cycle.
They
demonstrate that FGF receptors are present in the parenchyma as well as the vasculature of the CL
which suggests that FGF is involved in the regulation of luteal parenchymal and vascular function.
Berisha B, et al reported the expression and localization of fibroblast growth factor (FGF) family members during the final growth of bovine ovarian follicles.
.
The aim of this study was to investigate the possible participation of fibroblast growth factor (FGF) family members: FGF1, FGF2, and FGF7, and their receptor variants: FGFR, FGFR2IIIb, and FGFR2IIIc in theca interna (TI) and granulosa cell (GC) compartments of bovine follicles during final growth. A classification of follicles into five groups (<0.5; >0.5-5; >5-20; >20-180; >180 ng/ml, respectively) was performed according to the follicular fluid (FF) oestradiol-17beta (E) content. The mRNA expression and protein localization was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. FGF1 mRNA expression was relatively high in TI and lower in GC, and without any regulatory change for both tissue compartments during final follicular growth. The FGF1 protein could be predominantly localized in the cytoplasm of GC, in smooth muscle cells of blood vessels, in the rete ovarii, and at a lesser degree in theca cells. FGF2 mRNA in TI increased significantly in large follicles and was low and without any regulatory change in GC. FGF7 mRNA expression was relatively high in TI and very low in GC. For FGF7 in mature follicles a marked staining of the TI and the basal layers of the GC could be demonstrated. The mRNA signal for the FGFR in TI increased significantly with beginning of E production (E > 0.5-5 ng/ml FF) and was without any regulatory change in GC. The mRNA expression of FGFR2IIIb was relatively high in GC and increased significantly during final growth of follicles in contrast to the TI with very low expression. The FGFR2IIIc mRNA expression in TI and GC was relatively high but without any clear change. Our results suggest that FGF growth factor family members are involved in process of folliculogenesis and especially during final growth of the preovulatory (dominant) follicle by stimulation of angiogenesis and GC survival and proliferation.
The human cumulus-oocyte complex gene-expression profile. Assou S et al. BACKGROUND: The understanding of the mechanisms regulating human oocyte maturation is still rudimentary. We have identified transcripts differentially expressed between immature and mature oocytes and cumulus cells. METHODS: Using oligonucleotide microarrays, genome-wide gene expression was studied in pooled immature and mature oocytes or cumulus cells from patients who underwent IVF. RESULTS: In addition to known genes, such as DAZL, BMP15 or GDF9, oocytes up-regulated 1514 genes. We show that PTTG3 and AURKC are respectively the securin and the Aurora kinase preferentially expressed during oocyte meiosis. Strikingly, oocytes overexpressed previously unreported growth factors such as TNFSF13/APRIL, FGF9, FGF14 and IL4 and transcription factors including OTX2, SOX15 and SOX30. Conversely, cumulus cells, in addition to known genes such as LHCGR or BMPR2, overexpressed cell-to-cell signalling genes including TNFSF11/RANKL, numerous complement components, semaphorins (SEMA3A, SEMA6A and SEMA6D) and CD genes such as CD200. We also identified 52 genes progressively increasing during oocyte maturation, including CDC25A and SOCS7. CONCLUSION: The identification of genes that were up- and down-regulated during oocyte maturation greatly improves our understanding of oocyte biology and will provide new markers that signal viable and competent oocytes. Furthermore, genes found expressed in cumulus cells are potential markers of granulosa cell tumours.
FIBROBLAST GROWTH FACTOR-9, A LOCAL REGULATOR OF OVARIAN FUNCTION. Drummond AE et al. Fibroblast growth factor 9 (FGF9) is widely expressed in embryos and fetuses and has been shown to be involved in male sex determination, testicular cord formation and Sertoli cell differentiation. Given its male gender bias, the ovary has not been reported to express FGF9 nor has a role in ovarian function been explored. We report here, that FGF9 mRNA and protein are present in the rat ovary and provide evidence that supports a role for FGF9 in ovarian progesterone production. FGF9 mRNA levels as determined by real-time PCR, were high in 4 day old rat ovaries, thereafter declining and stabilising at levels approximately 30% of day 4 levels at days 12-25. Levels of FGF9 mRNA in the ovary were significantly higher than that present in adult testis, at all ages studied. The FGF9 receptors, FGFR2 and FGFR3 mRNAs were present in post natal and immature rat ovary and appeared to be constitutively expressed. FGF9 protein was localized to theca, stromal cells and corpora lutea and FGFR2 and FGFR3 proteins to granulosa cells, theca cells, oocytes and corpora lutea, by immunohistochemistry. Follicular differentiation induced by gonadotropin treatment reduced the expression of FGF9 mRNA by immature rat ovaries, whereas the estrogen stimulated development of large preantral follicles had no significant effect. In vitro, FGF9 stimulated progesterone production by granulosa cells beyond that elicited by a maximally stimulating dose of FSH. When the granulosa cells were pretreated with FSH to induce LH receptors, FGF9 was found not to be as potent as LH in stimulating progesterone production, nor did it enhance LH stimulated production. The combined treatments of FSH/FGF9 and FSH/LH however, were most effective at stimulating progesterone production by these differentiated granulosa cells. Analyses of steroidogenic regulatory proteins indicate that StAR and SCC mRNA levels were enhanced by FGF9 providing a mechanism of action for the increased progesterone synthesis. In summary, the data are consistent with a paracrine role for FGF9 in the ovary.
Expression of fibroblast growth factor 10 and its receptor, fibroblast growth factor receptor 2B, in the bovine corpus luteum. Castilho AC et al. There is evidence that several fibroblast growth factors (FGFs) are involved in growth and development of the corpus luteum (CL), but many FGFs have not been investigated in this tissue, including FGF10. The objective of this study was to determine if FGF10 and its receptor (FGFR2B) are expressed in the CL. Bovine CL were collected from an abattoir and classed as corpus hemorrhagica (stage I), developing (stage II), developed (stage III), and regressed (stage IV) CL. Expression of FGF10 and FGFR2B mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). Both genes were expressed in bovine CL, and FGF10 expression did not differ between stages of CL development. FGF10 protein was localized to large and small luteal cells by immunohistochemistry. FGFR2B expression was approximately threefold higher in regressed compared to developing and developed CL (P < 0.05). To determine if FGF10 and FGFR2B expression is regulated during functional luteolysis, cattle were injected with PGF2alpha and CL collected at 0, 0.5, 2, 4, 12, 24, 48, and 64 hr thereafter (n = 5 CL/time point), and mRNA abundance was measured by real-time RT-PCR. FGF10 mRNA expression did not change during functional luteolysis, whereas FGFR2B mRNA abundance decreased significantly at 2, 4, and 12 hr after PGF2alpha, and returned to pretreatment levels for the period 24-64 hr post-PGF2alpha. These data suggest a potential role for FGFR2B signaling during structural luteolysis in bovine CL. Mol. Reprod. Dev. (c) 2007 Wiley-Liss, Inc.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Expression of fibroblast growth factor 10 and cognate receptors in the developing bovine ovary. Castilho AC 2014 et al.
In the mammalian ovary, FGF10 is expressed in oocytes and theca cells and is a candidate for paracrine signaling to the developing granulosa cells. To gain insight into the participation of FGF10 in the regulation of fetal folliculogenesis, we assessed mRNA expression patterns of FGF10 and its receptors, FGFR1B and FGFR2B, in relation to fetal follicle dynamics and localized FGF10 protein in bovine fetal ovaries at different ages. Primordial, primary, secondary, and antral follicles were first observed on Days 75, 90, 150, and 210 of gestation, respectively. The levels of GDF9 and BMP15 mRNA, markers for primordial and primary follicles, respectively, increased during fetal ovary development in a consistent manner with fetal follicle dynamics. CYP17A1 mRNA abundance increased from Day 60 to Day 75 and then from Day 120 to Day 150, coinciding with the appearance of secondary follicles. FGF10 mRNA abundance increased from Day 90, and this increase was temporally associated with increases in FGFR1B mRNA abundance and in the population of primary follicles. In contrast, FGFR2B mRNA expression was highest on Day 60 and decreased thereafter. FGF10 protein was localized to oogonia and oocytes and surrounding granulosa cells at all fetal ages. The present data suggest a role for FGF10 in the control of fetal folliculogenesis in cattle.
/////////////////////////
Expression of Fibroblast Growth Factor 1 (FGF1) and FGF7 in Mature Follicles during the Periovulatory Period after GnRH in the Cow Berisha B, e al .
The aim of this study was to evaluate the expression pattern of mRNA for fibroblast growth factor 1 (FGF1), FGF7, and their receptor variants (FGFR2IIIb) in time-defined follicle classes before LH surge, between LH surge and ovulation, and in the early corpus luteum (CL) in the cow. The ovaries were collected by transvaginal ovariectomy (n=5 cows/group), and the follicles (n=5, one follicle/cow) were classified into the following groups: before GnRH administration (before LH surge); 3-5 h after GnRH (during LH surge); 10 h after GnRH; 20 h after GnRH; 25 h after GnRH (periovulation), and early CL (Days 2-3). The mRNA expression was analyzed by quantitative real-time PCR (RotorGene 3000). The mRNA expression of FGF1 showed no significant differences in the follicle groups examined, but increased significantly at the early CL phase. A transient increase in FGF7 mRNA expression was observed 3-5 h after GnRH and again in the early CL phase. In contrast, the expression of FGFR2IIIb was constant throughout the period from the final growth of the follicle to early CL formation. The results of this study suggest that FGF1 and FGF7 may be involved differently in the process of follicle maturation and CL formation, which is strongly dependent on angiogenesis.
FGF10 inhibits dominant follicle growth and estradiol secretion in vivo in cattle. Gasperin B et al. Fibroblast growth factors (FGFs) are involved in paracrine control of follicle development. It was previously demonstrated that FGF10 decreases estradiol secretion in granulosa cell culture and that theca cell FGF10 mRNA expression is decreased in healthy follicles from abattoir ovaries. The main objectives of the present study were to evaluate FGF10 and FGFR2b mRNA expression during follicular development in vivo, to evaluate the effect of FGF10 on follicle growth using Bos taurus taurus cows as a model and to gain more insight into the mechanisms through which FGF10 inhibits steroidogenesis. Messenger RNA encoding both FGF10 and FGFR2b (main FGF10 receptor) were significantly more expressed in subordinate follicles than in dominant follicles. The intrafollicular injection of FGF10 into the largest growing follicle at 7-8mm in diameter interrupted the dominant follicle growth in a dose dependent manner (11?0.4, 8.3?1 and 5.9?0.3mm for 0, 0.1 and 1?g/mL FGF10, at 72h after treatment; P<0.05). In a third experiment, follicles were obtained 24h after FGF10 (1?g/mL) or PBS treatment through ovariectomy. In theca cells, FGF10 treatment did not affect mRNA encoding steroidogenic enzymes, LHCGR and IGFBPs, but significantly upregulated FGF10 mRNA expression. The expression of CYP19A1 mRNA in granulosa cells was downregulated by FGF10 treatment, which was accompanied by a fifty-fold decrease in estradiol production, and decreased cyclin D2 mRNA. These results shown that FGF10 and its receptor FGFR2b are more expressed in subordinate follicles and provide solid in vivo evidence that FGF10 acts as an important regulator of follicular growth in cattle.
Phenotypes
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: fertile Comment:Passos-Bueno et al. (1999) provided an up-to-date listing of the mutations in FGFR1, FGFR2, and FGFR3 that are
associated with distinct clinical entities, including achondroplasia , hypochondroplasia , platyspondylic
lethal skeletal dysplasia , thanatophoric dysplasia , Antley-Bixler syndrome
, Apert syndrome , etc.